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Journal of Pharmacological Sciences Oct 2019Neurons extend axons far from cell bodies, and retrograde communications from distal axons to cell bodies and/or dendrites play critical roles in the development and... (Review)
Review
Neurons extend axons far from cell bodies, and retrograde communications from distal axons to cell bodies and/or dendrites play critical roles in the development and maintenance of neuronal circuits. In neurotrophin signaling, the retrograde axonal transport of endosomes containing active ligand-receptor complexes from distal axons to somatodendrite compartments mediates retrograde signaling. However, the generality and specificity of these endosome-based transportations called "signaling endosomes" remain to be elucidated. Here, I summarize the discovery of semaphorin3A signaling endosomes, the first example other than neurotrophins to regulate dendritic development via AMPA receptor GluA2 localization in dendrites. The molecular components of Sema3A and neurotrophin signaling endosomes are distinct, but partially overlap to regulate specific and common cellular events. Because receptors are transported back to the cell bodies, neurons must replenish receptors on the growth cone surface to ensure continued response to the target-derived ligands. Recent findings have demonstrated that retrograde signaling endosomes also induce anterograde delivery of nascent receptors in neurotrophin signaling. The coupling between anterograde and retrograde axonal transport via signaling endosomes therefore plays a critical role in regulating proper neuronal network formation.
Topics: Animals; Axonal Transport; Axons; Cell Communication; Endosomes; Humans; Nerve Growth Factors; Protein Transport; Receptors, AMPA; Retrograde Degeneration; Semaphorin-3A; Signal Transduction
PubMed: 31679963
DOI: 10.1016/j.jphs.2019.10.001 -
Biochemical Society Transactions Oct 2020The conformation with which natural agonistic peptides interact with G protein-coupled receptor(s) (GPCR(s)) partly results from intramolecular interactions such as... (Review)
Review
The conformation with which natural agonistic peptides interact with G protein-coupled receptor(s) (GPCR(s)) partly results from intramolecular interactions such as hydrogen bridges or is induced by ligand-receptor interactions. The conformational freedom of a peptide can be constrained by intramolecular cross-links. Conformational constraints enhance the receptor specificity, may lead to biased activity and confer proteolytic resistance to peptidic GPCR agonists. Chemical synthesis allows to introduce a variety of cross-links into a peptide and is suitable for bulk production of relatively simple lead peptides. Lanthionines are thioether bridged alanines of which the two alanines can be introduced at different distances in chosen positions in a peptide. Thioether bridges are much more stable than disulfide bridges. Biosynthesis of lanthionine-constrained peptides exploiting engineered Gram-positive or Gram-negative bacteria that contain lanthionine-introducing enzymes constitutes a convenient method for discovery of lanthionine-stabilized GPCR agonists. The presence of an N-terminal leader peptide enables dehydratases to dehydrate serines and threonines in the peptide of interest after which a cyclase can couple the formed dehydroamino acids to cysteines forming (methyl)lanthionines. The leader peptide also guides the export of the formed lanthionine-containing precursor peptide out of Gram-positive bacteria via a lanthipeptide transporter. An engineered cleavage site in the C-terminus of the leader peptide allows to cleave off the leader peptide yielding the modified peptide of interest. Lanthipeptide GPCR agonists are an emerging class of therapeutics of which a few examples have demonstrated high efficacy in animal models of a variety of diseases. One lanthipeptide GPCR agonist has successfully passed clinical Phase Ia.
Topics: Alanine; Animals; Anti-Bacterial Agents; Bacterial Proteins; Disulfides; Drug Discovery; GTP-Binding Proteins; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Lanthanoid Series Elements; Membrane Transport Proteins; Mice; Peptide Hydrolases; Peptides; Protein Domains; Protein Processing, Post-Translational; Protein Sorting Signals; Rats; Receptors, G-Protein-Coupled; Substrate Specificity; Sulfides
PubMed: 33125486
DOI: 10.1042/BST20200427 -
Trends in Immunology May 2022The essentially monomorphic human antigen presentation molecule HLA-E is an interesting candidate target to enable vaccination irrespective of genetic diversity.... (Review)
Review
The essentially monomorphic human antigen presentation molecule HLA-E is an interesting candidate target to enable vaccination irrespective of genetic diversity. Predictive HLA-E peptide-binding motifs have been refined to facilitate HLA-E peptide discovery. HLA-E can accommodate structurally divergent peptides of both self and microbial origin. Intracellular processing and presentation pathways for peptides by HLA-E for T cell receptor (TCR) recognition remain to be elucidated. Recent studies show that, unlike canonical peptides, inhibition of the transporter associated with antigen presentation (TAP) is essential to allow HLA-E antigen presentation in cytomegalovirus (CMV) infection and possibly also of other non-canonical peptides. We propose three alternative and TAP-independent MHC-E antigen-presentation pathways, including for Mycobacterium tuberculosis infections. These insights may help in designing potential HLA-E targeting vaccines against tumors and pathogens.
Topics: Antigen Presentation; Histocompatibility Antigens Class I; Humans; Membrane Transport Proteins; Peptides; Tuberculosis; Vaccination
PubMed: 35370095
DOI: 10.1016/j.it.2022.03.002 -
The Journal of Cell Biology Jul 2023Mitochondria critically rely on protein import and its tight regulation. Here, we found that the complex I assembly factor NDUFAF8 follows a two-step import pathway...
Mitochondria critically rely on protein import and its tight regulation. Here, we found that the complex I assembly factor NDUFAF8 follows a two-step import pathway linking IMS and matrix import systems. A weak targeting sequence drives TIM23-dependent NDUFAF8 matrix import, and en route, allows exposure to the IMS disulfide relay, which oxidizes NDUFAF8. Import is closely surveyed by proteases: YME1L prevents accumulation of excess NDUFAF8 in the IMS, while CLPP degrades reduced NDUFAF8 in the matrix. Therefore, NDUFAF8 can only fulfil its function in complex I biogenesis if both oxidation in the IMS and subsequent matrix import work efficiently. We propose that the two-step import pathway for NDUFAF8 allows integration of the activity of matrix complex I biogenesis pathways with the activity of the mitochondrial disulfide relay system in the IMS. Such coordination might not be limited to NDUFAF8 as we identified further proteins that can follow such a two-step import pathway.
Topics: Disulfides; Electron Transport Complex I; Endopeptidases; Mitochondria; Peptide Hydrolases; Biological Transport
PubMed: 37159021
DOI: 10.1083/jcb.202210019 -
Proceedings of the National Academy of... Feb 2022Autophagy is a fundamental cellular process of protein degradation and recycling that regulates immune signaling pathways via multiple mechanisms. However, it remains...
Autophagy is a fundamental cellular process of protein degradation and recycling that regulates immune signaling pathways via multiple mechanisms. However, it remains unclear how autophagy epigenetically regulates the immune response. Here, we identified TRIM14 as an epigenetic regulator that reduces histone H3K9 trimethylation by inhibiting the autophagic degradation of the histone demethylase KDM4D. TRIM14 recruited the deubiquitinases USP14 and BRCC3 to cleave the K63-linked ubiquitin chains of KDM4D, which prevented KDM4D from undergoing optineurin (OPTN)-mediated selective autophagy. Tripartite motif-containing 14 (TRIM14) deficiency in dendritic cells significantly impaired the expression of the KDM4D-directed proinflammatory cytokines interleukin 12 () and and protected mice from autoimmune inflammation. Taken together, these findings highlight the cross-talk between epigenetic regulation and autophagy and suggest TRIM14 is a potential target of therapeutic intervention for inflammation-related diseases.
Topics: Animals; Autophagy; Cell Cycle Proteins; Encephalomyelitis, Autoimmune, Experimental; Epigenesis, Genetic; Female; Gene Expression Regulation; Inflammation; Intracellular Signaling Peptides and Proteins; Jumonji Domain-Containing Histone Demethylases; Membrane Transport Proteins; Mice; Mice, Knockout; Specific Pathogen-Free Organisms; Tripartite Motif Proteins
PubMed: 35145029
DOI: 10.1073/pnas.2113454119 -
International Journal of Molecular... May 2023Enteroendocrine cells are specialized secretory lineage cells in the small and large intestines that secrete hormones and peptides in response to luminal contents. The... (Review)
Review
Enteroendocrine cells are specialized secretory lineage cells in the small and large intestines that secrete hormones and peptides in response to luminal contents. The various hormones and peptides can act upon neighboring cells and as part of the endocrine system, circulate systemically via immune cells and the enteric nervous system. Locally, enteroendocrine cells have a major role in gastrointestinal motility, nutrient sensing, and glucose metabolism. Targeting the intestinal enteroendocrine cells or mimicking hormone secretion has been an important field of study in obesity and other metabolic diseases. Studies on the importance of these cells in inflammatory and auto-immune diseases have only recently been reported. The rapid global increase in metabolic and inflammatory diseases suggests that increased understanding and novel therapies are needed. This review will focus on the association between enteroendocrine changes and metabolic and inflammatory disease progression and conclude with the future of enteroendocrine cells as potential druggable targets.
Topics: Intestines; Enteroendocrine Cells; Biological Transport; Peptides; Hormones
PubMed: 37240181
DOI: 10.3390/ijms24108836 -
Molecular Microbiology May 2020The twin-arginine protein transport (Tat pathway) is found in prokaryotes and plant organelles and transports folded proteins across membranes. Targeting of substrates... (Review)
Review
The twin-arginine protein transport (Tat pathway) is found in prokaryotes and plant organelles and transports folded proteins across membranes. Targeting of substrates to the Tat system is mediated by the presence of an N-terminal signal sequence containing a highly conserved twin-arginine motif. The Tat machinery comprises membrane proteins from the TatA and TatC families. Assembly of the Tat translocon is dynamic and is triggered by the interaction of a Tat substrate with the Tat receptor complex. This review will summarise recent advances in our understanding of Tat transport, focusing in particular on the roles played by Tat signal peptides in protein targeting and translocation.
Topics: Amino Acid Motifs; Bacterial Proteins; Cell Membrane; Escherichia coli Proteins; Membrane Transport Proteins; Protein Binding; Protein Conformation; Protein Sorting Signals; Protein Transport; Twin-Arginine-Translocation System
PubMed: 31971282
DOI: 10.1111/mmi.14461 -
Nature Mar 2022The membrane translocation of hydrophilic substances constitutes a challenge for their application as therapeutic compounds and labelling probes. To remedy this, charged...
The membrane translocation of hydrophilic substances constitutes a challenge for their application as therapeutic compounds and labelling probes. To remedy this, charged amphiphilic molecules have been classically used as carriers. However, such amphiphilic carriers may cause aggregation and non-specific membrane lysis. Here we show that globular dodecaborate clusters, and prominently BBr, can function as anionic inorganic membrane carriers for a broad range of hydrophilic cargo molecules (with molecular mass of 146-4,500 Da). We show that cationic and neutral peptides, amino acids, neurotransmitters, vitamins, antibiotics and drugs can be carried across liposomal membranes. Mechanistic transport studies reveal that the carrier activity is related to the superchaotropic nature of these cluster anions. We demonstrate that BBr affects cytosolic uptake of different small bioactive molecules, including the antineoplastic monomethyl auristatin F, the proteolysis targeting chimera dBET1 and the phalloidin toxin, which has been successfully delivered in living cells for cytoskeleton labelling. We anticipate the broad and distinct delivery spectrum of our superchaotropic carriers to be the starting point of conceptually distinct cell-biological, neurobiological, physiological and pharmaceutical studies.
Topics: Anions; Biological Transport; Boron; Cations; Drug Carriers; Hydrophobic and Hydrophilic Interactions; Peptides; Pharmaceutical Preparations
PubMed: 35322251
DOI: 10.1038/s41586-022-04413-w -
The Protein Journal Aug 2019The twin-arginine protein translocation (Tat) system has been characterized in bacteria, archaea and the chloroplast thylakoidal membrane. This system is distinct from... (Review)
Review
The twin-arginine protein translocation (Tat) system has been characterized in bacteria, archaea and the chloroplast thylakoidal membrane. This system is distinct from other protein transport systems with respect to two key features. Firstly, it accepts cargo proteins with an N-terminal signal peptide that carries the canonical twin-arginine motif, which is essential for transport. Second, the Tat system only accepts and translocates fully folded cargo proteins across the respective membrane. Here, we review the core essential features of folded protein transport via the bacterial Tat system, using the three-component TatABC system of Escherichia coli and the two-component TatAC systems of Bacillus subtilis as the main examples. In particular, we address features of twin-arginine signal peptides, the essential Tat components and how they assemble into different complexes, mechanistic features and energetics of Tat-dependent protein translocation, cytoplasmic chaperoning of Tat cargo proteins, and the remarkable proofreading capabilities of the Tat system. In doing so, we present the current state of our understanding of Tat-dependent protein translocation across biological membranes, which may serve as a lead for future investigations.
Topics: Arginine; Bacillus subtilis; Cell Membrane; Escherichia coli; Escherichia coli Proteins; Membrane Transport Proteins; Protein Folding; Protein Sorting Signals; Protein Transport; SEC Translocation Channels; Twin-Arginine-Translocation System
PubMed: 31401776
DOI: 10.1007/s10930-019-09859-y -
Biomolecules Jan 2021Cell plasma membrane proteins are considered as gatekeepers of the cell and play a major role in regulating various processes. Transport proteins constitute a subclass... (Review)
Review
Cell plasma membrane proteins are considered as gatekeepers of the cell and play a major role in regulating various processes. Transport proteins constitute a subclass of cell plasma membrane proteins enabling the exchange of molecules and ions between the extracellular environment and the cytosol. A plethora of human pathologies are associated with the altered expression or dysfunction of cell plasma membrane transport proteins, making them interesting therapeutic drug targets. However, the search for therapeutics is challenging, since many drug candidates targeting cell plasma membrane proteins fail in (pre)clinical testing due to inadequate selectivity, specificity, potency or stability. These latter characteristics are met by nanobodies, which potentially renders them eligible therapeutics targeting cell plasma membrane proteins. Therefore, a therapeutic nanobody-based strategy seems a valid approach to target and modulate the activity of cell plasma membrane transport proteins. This review paper focuses on methodologies to generate cell plasma membrane transport protein-targeting nanobodies, and the advantages and pitfalls while generating these small antibody-derivatives, and discusses several therapeutic nanobodies directed towards transmembrane proteins, including channels and pores, adenosine triphosphate-powered pumps and porters.
Topics: Antigens; Cell Membrane; Humans; Membrane Transport Proteins; Models, Biological; Single-Domain Antibodies
PubMed: 33418902
DOI: 10.3390/biom11010063